The objective of this career development award is to provide the candidate, Dr. Francisco J. Esteva, the experience and knowledge necessary to direct an independent patient-oriented research program. Dr. Esteva is a medical oncologist with five years of clinical training and two years of basic research training, including experience with animal models of human breast cancer. He currently devotes 20 percent of his effort to research and 80 percent to clinical activities. This award would enable the candidate to increase his research effort to 75 percent. The specific aim of this proposal are: (1) to determine the pharmacokinetics, dose-limiting toxicity, maximum tolerated dose (MTD), or biologically active dose (BAD) of liposomal antisense to Bcl-2 (L-Bc1-2 AS) for patients with solid tumors; (2) to determine the efficacy of L-Bcl-2 AS in combination with docetaxel for patients with breast cancer resistant to paclitaxel; and (3) to investigate the efficacy of docetaxel, paclitaxel and doxorubicin in combination with L-Bcl-2 AS in animal models of human breast cancer. Research design and methods. Dr. Esteva will conduct a phase I trial of L-Bcl-2 AS in patients with metastatic solid tumors. The MTD is defined as the dose at which two of six patients experience grade 3 or higher toxicity. BAD is defined as the dose associated with a 50 percent reduction in Bcl-2 expression in circulating lymphoma cells (flow cytometry) or a 50 percent reduction in Bcl-2 expression in tumor biopsies (immunohistochemistry or western blot). It is anticipated that this study will accrue 21-24 patients in approximately 24 months. The second aim will be addressed by a phase I/II clinical trial. Efficacy will be measured by the rate of response. The trial will be conducted in two stages. Thirteen patients will be entered in the first stage and 30 in the second stage, for a total of 43 patients. It is anticipated this study will take approximately three years. The trial design assumes type I and type II error rates of 5 percent and 20 percent, respectively. Human breast cancer MCF-7 xenografts will also be developed in nude mice and Severe Combined Immunodeficiency (SCID) mice. MCF-7 cells overexpressess Bcl-2 and grow readily as xenografts in mice. The Candidate will be supervised by Dr. Gabriel Hortobagyi (Department of Breast Medical Oncology) and Dr. Gabriel Lopez-Berestein (Department of Bioimmunotherapy). M. D. Anderson Cancer Center has the patients and resources necessary for Dr. Esteva to successfully complete this research project.